Adrenergic Receptors in Alzheimer’s Disease Brain: Selective Increases in the Cerebella of Aggressive Patients

Russo-Neustadt, Amelia; Cotman, Carl W.

doi:10.1523/jneurosci.17-14-05573.1997

Cited by 83 publications

(42 citation statements)

References 39 publications

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“…This differential impact is consistent with prior studies indicating that cognitive performance can be improved in rodents independently of aggression [57,58]. Similarly, while both cognitive impairment and aggression accompany AD, they are not necessarily temporally colocalized and may but do not necessarily respond to identical treatments [59][60][61][62]. These behavioral manifestations in mice are directly relevant since AD can be accompanied by psychosis and agitation [63], and ApoE4 can also potentiate psychotic symptoms in humans [64].…”

Section: Nutritional Deficiency Potentiates the Impact Of Deficiency supporting

confidence: 86%

Apolipoprotein E3 as a Risk Factor for Alzheimer's Disease Under Conditions of Nutritional Imbalance

Chan

Shea

2010

JAD

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Abstract. The presence of one or more copies of the E4 allele of apolipoprotein E (ApoE) is strongly associated with of Alzheimer's disease (AD). The impact of E4 on neurodegeneration is potentiated by dietary oxidative challenge. Our prior studies in transgenic mice demonstrate that, in the face of dietary oxidative challenge, E3 does not provide any further protection than E4 or lack of murine ApoE for aggression, oxidative damage, presenilin-1 expression, and γ-secretase activity, and provides only partial reduction in phospho-tau levels. Extrapolation of these findings to the human condition leads us to hypothesize that the E3 allele may not provide sufficient neuroprotection under conditions of dietary compromise and/or oxidative challenge. Epidemiological evidence is consistent with this possibility. The E3 allele is approximately half as effective compared to E2 at buffering the impact of a single E4 allele. In addition, the risk of AD increases linearly for the genotypes E2/2, E2/3, and E3/3. It has been proposed that that clinical manifestation of AD may in some cases require the convergence of 2 or more risk factors. We hypothesize that the combined impact of dietary oxidative stress and either the ApoE3 or E4 genotype represents one such condition.Keywords: Alzheimer's disease, apolipoprotein E, diet, nutritional deficiency, oxidative stresss APOE, OXIDATIVE DAMAGE, AND ALZHEIMER'S DISEASEA major risk factor for Alzheimer's disease (AD) is the presence of the E4 allele of apolipoprotein E (ApoE), which accounts for up to 50% of the cases of AD [1][2][3][4][5]. Considerable effort has been devoted to determining the nature and extent of risk imparted by ApoE4 and what might be done to lessen this risk [6]. Oxidative damage represents an early and perhaps pivotal factor contributing to age-related decline in cogni- * Correspondence to: Thomas B. Shea, Center for Cellular Neurobiology and Neurodegeneration Research, UMassLowell, Lowell, Massachusetts 01854, USA. Tel.: +1 978 934 2881; Fax: +1 978 934 3044; E-mail: Thomas Shea@uml.edu. tive performance including that associated with AD [7][8][9][10][11][12]. Oxidative damage and ApoE4 are inter-related, as the extent of brain oxidative damage in AD is correlated with the presence of E4 [13][14][15][16]. ApoE mediates transport and clearance of lipids, including those subjected to oxidative damage. In doing so, ApoE prevents a cascade of neuronal oxidative damage by quenching downstream products of lipid oxidation, preventing secondary glutamate excitotoxicity and sequestering oxidative metals such as iron [4,17,18,20]. However, ApoE4 is thought to be less effective at this latter function [21].While over 20 other genes are suspected of being related to AD [22], deficiency in ApoE function has a particularly far-reaching impact in that it not only impairs overall brain metabolism and may impair compensato-

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Section: Nutritional Deficiency Potentiates the Impact Of Deficiency supporting

confidence: 86%

Apolipoprotein E3 as a Risk Factor for Alzheimer's Disease Under Conditions of Nutritional Imbalance

Chan

Shea

2010

JAD

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“…36 Regarding the adrenergic system, it has been shown that patients with AD who display aggressive behaviors have a markedly higher level of ␣ 2 , ␤ 1 , and ␤ 2 adrenergic receptors in the cerebellar cortex. 37 There is also a relative preservation of inhibitory noradrenergic neuronal input to the cerebellar cortex (tyrosine hydroxylasepositive neuronal fibers) in patients with AD who exhibit aggressive behavior. 38 Regarding the serotoninergic system, loss of serotonin 2 (5-HT 2 ) receptors in multiple cortical areas 39 and reduced density of 5-HT 1A receptors in temporal areas 40 has been reported for patients with AD who manifest aggressive behavior.…”

Section: Commentmentioning

confidence: 99%

Disruptive Behavior as a Predictor in Alzheimer Disease

Scarmeas¹,

Brandt²,

Blacker

et al. 2007

Arch Neurol

141

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Background: Disruptive behavior is common in Alzheimer disease (AD). There are conflicting reports regarding its ability to predict cognitive decline, functional decline, institutionalization, and mortality.Objective: To examine whether the presence of disruptive behavior has predictive value for important outcomes in AD.Design: Using the Columbia University Scale for Psychopathology in Alzheimer Disease (administered every 6 months, for a total of 3438 visit-assessments and an average of 6.9 per patient), the presence of disruptive behavior (wandering, verbal outbursts, physical threats/violence, agitation/restlessness, and sundowning) was extracted and examined as a timedependent predictor in Cox models. The models controlled for the recruitment cohort, recruitment center, informant status, sex, age, education, a comorbidity index, baseline cognitive and functional performance, and neuroleptic use. Setting: Five university-based AD centers in the United States and Europe (Predictors Study). Participants: Four hundred ninety-seven patients with early-stage AD (mean Folstein Mini-Mental State Examination score, 20 of 30 at entry) who were recruited and who underwent semiannual follow-up for as long as 14 (mean, 4.4) years. Main Outcome Measures: Cognitive (Columbia Mini-Mental State Examination score, Յ 20 of 57 [approximate Folstein Mini-Mental State Examination score, Յ10 of 30]) and functional (Blessed Dementia Rating Scale score, parts I and II, Ն 10) ratings, institutionalization equivalent index, and death.Results: At least 1 disruptive behavioral symptom was noted in 48% of patients at baseline and in 83% at any evaluation. Their presence was associated with increased risks of cognitive decline (hazard ratio 1.45 [95% confidence interval (CI), 1.03-2.03]), functional decline (1.66 [95% CI, 1.17-2.36]), and institutionalization (1.47 [95% CI, 1.10-1.97]). Sundowning was associated with faster cognitive decline, wandering with faster functional decline and institutionalization, and agitation/restlessness with faster cognitive and functional decline. There was no association between disruptive behavior and mortality (hazard ratio, 0.94 [95% CI, 0.71-1.25]). Conclusion:Disruptive behavior is very common in AD and predicts cognitive decline, functional decline, and institutionalization but not mortality.

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“…α 2 -Adrenergic receptors have been reported as either unaltered [402] or reduced [403][404][405] in frontal cortex of Alzheimer patients. However, the preservation or decrease of α 2 -adrenergic receptors in brain tissue occurs in spite of a large increase in α 2 -adrenergic receptors in cerebral microvessels [406].…”

Section: Alzheimer's Diseasementioning

confidence: 99%

“…Accordingly the density of parenchymal α 2 -receptors must be decreased. Available evidence regarding other noradrenergic receptors is less consistent [402,[407][408][409]. MAO B increases during normal aging, but is overexpressed in Alzheimer's brains, compared to agematched controls [410][411][412], at least partly reflecting that MAO B is associated with fibrillary astrocytes in and around amyloid plaques [413].…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Astrocytic Adrenoceptors: A Major Drug Target in Neurological and Psychiatric Disorders?

Hertz¹,

Chen²,

Gibbs³

et al. 2004

CDTCNSND

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Considerable attention has recently been paid to astrocyte functions, which are briefly summarized. A large amount of data is available about adrenoceptor expression and function in astrocytes, some of it dating back to the 1970's and some of it very recent. This material is reviewed in the present paper. The brain is innervated by noradrenergic fibers extending from locus coeruleus in the brain stem, which in turn is connected to a network of adrenergic and noradrenergic nuclei in the medulla and pons, contributing to the control of (nor)adrenergic, serotonergic, dopaminergic and cholinergic function, both in the central nervous system (CNS) and in the periphery. In the CNS astrocytes constitute a major target for noradrenergic innervation, which regulates morphological plasticity, energy metabolism, membrane transport, gap junction permeability and immunological responses in these cells. Noradrenergic effects on astrocytes are essential during consolidation of episodal, long-term memory, which is reinforced by β-adrenergic activation. Glycogenolysis and synthesis of glutamate and glutamine from glucose, both of which are metabolic processes restricted to astrocytes, occurs at several time-specific stages during the consolidation. Astrocytic abnormalities are almost certainly important in the pathogenesis of multiple sclerosis and in all probability contribute essentially to inflammation and malfunction in Alzheimer's disease and to mood disturbances in affective disorders. Noradrenergic function in astrocytes is severely disturbed by chronic exposure to cocaine, which also changes astrocyte morphology. Development of drugs modifying noradrenergic receptor activity and/or down-stream signaling is advocated for treatment of several neurological/psychiatric disorders and for neuroprotection. Astrocytic preparations are suggested for study of mechanism(s) of action of antidepressant drugs and pathophysiology of mood disorders.

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Adrenergic Receptors in Alzheimer’s Disease Brain: Selective Increases in the Cerebella of Aggressive Patients

Cited by 83 publications

References 39 publications

Apolipoprotein E3 as a Risk Factor for Alzheimer's Disease Under Conditions of Nutritional Imbalance

Apolipoprotein E3 as a Risk Factor for Alzheimer's Disease Under Conditions of Nutritional Imbalance

Disruptive Behavior as a Predictor in Alzheimer Disease

Astrocytic Adrenoceptors: A Major Drug Target in Neurological and Psychiatric Disorders?

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